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Review ArticleAccuracy Evaluation of Circular RNA in Diagnosing LungCancer in a Chinese Population
Zhihao Xiao , Xinglei Chen , Xiaodan Lu, Xuexin Zhong , and Yihui Ling
Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, China
Correspondence should be addressed to Yihui Ling; [email protected]
Received 13 May 2019; Revised 17 August 2019; Accepted 5 September 2019; Published 20 October 2019
Academic Editor: Chiara Nicolazzo
Copyright © 2019 Zhihao Xiao et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Circular RNA (circRNA) is a class of recently discovered noncoding RNA. circRNAs can be used as a potent noninvasive biologicalmarker of cancer owing to their varying expression levels among different cancers. This meta-analysis was performed to assess theaccuracy of circRNAs in diagnosing lung cancer. A total of eight studies identified through searching the PubMed, Web of Science,Cochrane Library, and Embase from inception to March 20, 2019 were eligible for this meta-analysis. The pooled sensitivity,specificity, positive likelihood ratios, negative likelihood ratios, and diagnostic odds ratio were 0.77 (95% confidence interval(CI): 0.73–0.80; I2 = 8:98%), 0.76 (95% CI: 0.69–0.82; I2 = 63:12%), 3.17 (95% CI: 2.43–4.14; I2 = 33:18%), 0.31 (95% CI: 0.26–0.37; I2 = 20:36%), and 10.26 (95% CI: 6.87–15.31; I2 = 97:18%), respectively. The area under the receiver operatingcharacteristic curve was 0.78 (95% CI: 0.74–0.81). The study confirmed the use of circRNAs in diagnosing lung cancer in aChinese population.
1. Introduction
Circular RNA (circRNA) is a circular single-strand RNA firstdiscovered in plants [1, 2] and abundant in human cells. Insome cases, the abundance of circRNAs exceeds that of asso-ciated linear mRNAs by more than tenfold [3]. CircRNAslack free ends, 5′ cap, and 3′ poly(A) tail and are more stablethan linear RNAs with their ends joining in a circle via phos-phodiester bonds [4]. CircRNAs have many functionsincluding regulating gene transcription and translation viabinding to miRNAs, interacting with proteins, and beingdirectly translated [5]. Recent studies suggested significantadvantages of circRNAs in diagnosing cancers owing to theirprevalence, stability, specificity, and conservatism [6].
Experiments proved that circRNAs were associated withproliferation, apoptosis, invasion, and migration of tumorcells, and the expression varied with tumor cells, thus helpingin diagnosing and predicting the prognosis of tumors. Li et al.[7] found that Hsa_circ_0000096 was significantly downreg-ulated in gastric cancer tissues and cell lines and was associ-ated with the invasion and staging of tumors. Ma et al. [8]
reported that circRNA-000284 was significantly higher incervical cancer cells than in cervical epithelial cells and couldserve as a biological marker. Li et al. [9] considered cir-cHIPK3 as the novel therapeutic target of bladder carcinoma.Some meta-analyses summarizing the role of circRNAs ondiagnosis and prognosis were reported [10–13]. Huanget al. [10] investigated the prognostic and diagnostic signifi-cance of the expression of circRNAs in patients with hepato-cellular carcinoma. Wang et al. [11], Li et al. [12], and Ding[13] performed a meta-analysis on the value of circRNAs asa biological marker of tumors. However, they just exploredthe role of circRNAs in diagnosing tumors but not speciallyor independently diagnosing lung cancer.
Lung cancer accounts for 25% of cancer-related deathsworldwide, which is much higher compared with other can-cers such as breast carcinoma, prostatic carcinoma, and colo-rectal carcinoma. The survival rate of patients with lungcancer is relatively low, possibly due to the lack of early test-ing methods [14]. The role of circRNAs in lung cancer wasfirst reported in 2018 by Qu et al. [5] who found that hsa_circ_00013958 promoted the proliferation, invasion, and
HindawiDisease MarkersVolume 2019, Article ID 7485389, 8 pageshttps://doi.org/10.1155/2019/7485389
metastasis of lung adenocarcinoma cells. A large number ofrecent studies explored the relationship between circRNAsand lung cancer [15–21].
2. Materials and Methods
2.1. Literature Search. Electronic databases, includingPubMed, Web of Science, Cochrane Library, and Embase,were systematically searched from inception to March 20,2019. The following search terms were used: circRNA, circu-lar RNA, lung cancer, lung neoplasm, lung adenocarcinoma,non-small-cell lung cancer, NSCLC, pulmonary cancer, andpulmonary neoplasm. In addition, the reference lists of eligi-ble studies were manually searched to guarantee the compre-hensiveness of the literature.
2.2. Inclusion and Exclusion Criteria. The inclusion criteriawere as follows: (1) studies analyzing the relationshipbetween circRNAs and lung cancer, (2) studies providingdata on the sensitivity and specificity, and (3) studies involv-ing ≥30 patients and controls. The exclusion criteria were asfollows: (1) repetitive research; (2) letters, editorials, com-mentaries, or abstracts; (3) studies involving ineligiblepatients or controls; (4) studies lacking data; or (5) studiesin a non-English language. If the results came from the over-lapping population, only the first study or the most completestudy was included.
2.3. Data Extraction and Quality Assessment. Two reviewers(Xuexin Zhong and Zhihao Xiao) extracted data. The dis-crepancies were resolved by the third reviewer (XiaodanLu) if needed. The following information was extracted fromeach study: first author name, year of publication, country,sample size, sample type, sensitivity, specificity, area underthe receiver operating characteristic (ROC) curve (AUC),
testing methods, tumor staging, reference gene, and differen-tial expression of circRNAs.
2.4. Statistical Analysis. Stata 12.0 software and Meta-DiSc1.4 were used for statistical analysis. The sensitivity, specific-ity, positive likelihood ratio (PLR), negative likelihood ratio(NLR), diagnostic odds ratio (DOR), 95% confidential inter-vals (95% CI), summary ROC (SROC) curve, and AUC werecalculated for quality assessment. The significance level wasset as P < 0:05. The heterogeneity induced by the thresholdeffect of included studies was tested using the Spearman cor-relation analysis. Cochran’sQ and I2 tests were used to assessthe heterogeneity of data. I2 > 50% indicated significant het-erogeneity. A subgroup analysis was performed based onsample type, cancer type, reference gene type, and differentialexpression of circRNAs. The potential source of heterogene-ity by the nonthreshold effect was analyzed by regressionanalysis. A Fagan nomogram was used to calculate the post-test probabilities. Finally, publication bias was assessed.
3. Results
3.1. Search Results. The flowchart of the study selection pro-cess is shown in Figure 1. The review of the literature identi-fied 388 studies, of which 209 repeated ones were excludedand the remaining 179 ones were screened based on titlesand abstracts. Subsequently, 165 studies, including reviews,letters, conference abstracts, and 2 studies on hsa_circ_0102533 [22] and circFARSA [23], were further excluded,owing to the inability of constructing a 2 × 2 contingencytable. A total of 8 studies [15–21, 24] and 10 eligible studies,involving 668 patients with lung cancer and 153 healthy con-trols, were assessed during this meta-analysis. The character-istics of eight studies are shown in Table 1. Surprisingly, alleight studies identified using search terms, inclusion criteria,and exclusion criteria were performed in China.
Iden
tifica
tion
Scre
enin
gEl
igib
ility
Incl
uded
Records a�er removing duplicates(n = 179)
Full-text studiesexcluded:
Studies with insufficient data to construct a 2 ⨯ 2 table Studies included in quantitative synthesis
(meta-analysis)
Records excluded:
Reviews, letters, conference abstracts, and
irrelevant studies with respect to circRNAs or lung malignancy Full-text articles assessed for eligibility
(n = 10)
Records identified throughdatabase search (n = 387)
Additional records identifiedthrough other sources (n = 1)
Figure 1: Flow chart of the study selection process.
2 Disease Markers
Table1:Characteristics
ofeightstud
iesinclud
edin
themeta.
Autho
rYear
circRNAs
Cou
ntry
Sampletype
No.of
cases
No.of
controls
AUC
Sensitivity
Specificity
Testing
metho
dTNM
staging
circRNA
expression
References
I–II
III–IV
Zhu
etal.
2017
hsa_circ_0013958
China
Blood
3030
0.794
0.667
0.933
qRT-PCR
2821
Upregulated
[24]
Lietal.
2018
hsa_circ_0079530
China
Tissue
9292
0.756
0.762
0.721
qRT-PCR
——
Upregulated
[15]
Zon
getal.
2018
circRNAs_102231
China
Tissue
5757
0.897
0.812
0.887
qRT-PCR
3027
Upregulated
[16]
Zhang
etal.2018
hsa_circ_0014130
China
Tissue
4646
0.878
0.87
0.848
qRT-PCR
3610
Upregulated
[17]
Zhang
etal.2018
circ_F
OXO3
China
Tissue
4545
0.782
0.8
0.733
qRT-PCR
——
Dow
nregulated
[18]
Lietal.
2018
circ_P
VT1
China
Blood
4545
0.794
0.711
0.8
qRT-PCR
3137
Upregulated
[19]
China
Tissue
6868
0.803
0.825
0.675
qRT-PCR
3137
Upregulated
Chenetal.
2019
circRNAs_100146
China
Tissue
4040
0.643
0.725
0.575
qRT-PCR
——
Upregulated
[20]
Liuetal.
2019
hsa_circ_0005962
China
Blood
153
540.73
0.719
0.7222
qRT-PCR
9655
Upregulated
[21]
hsa_circ_0086414
China
Blood
153
540.78
0.7712
0.6667
qRT-PCR
9655
Dow
nregulated
Note:data
notextracted;
AUC:areaun
derthereceiver
operatingcharacteristiccurve.
3Disease Markers
Study ID Specificity (95% CI)Specificity (95% CI)
Specificity
0.77 [0.70 - 0.84] 0.67 [0.53 - 0.79]
0.68 [0.55 - 0.78]
0.93 [0.78 - 0.99]
0.72 [0.58 - 0.84]
0.57 [0.41 - 0.73]
0.80 [0.65 - 0.90]
0.73 [0.58 - 0.85]
0.85 [0.71 - 0.94]
0.88 [0.76 - 0.95]
0.72 [0.61 - 0.81]
0.76 [0.69 - 0.82]
Q = 24.40, df = 9.00, P = 0.00
I2 = 63.12 [37.94 - 88.30]
0.82 [0.71 - 0.91]
0.67 [0.47 - 0.83]
0.72 [0.64 - 0.79]
0.73 [0.56 - 0.85]
0.71 [0.56 - 0.84]
0.80 [0.65 - 0.90]
0.87 [0.74 - 0.95]
0.81 [0.68 - 0.90]
0.76 [0.66 - 0.84]
0.77 [0.73 - 0.80]
Q = 9.89, df = 9.00, P = 0.36
I2 = 8.98 [0.00 - 97.95]
Study ID
Liu et al/2019
Liu et al/2019
Chen et al/2019
Li et al/2018
Zhang et al/2018
Zhang et al/2018
Zong et al/2018
Li et al/2018
Combined
0.5 1.0 1.00.4
Sensitivity
Li et al/2018
Zhu et al/2017
Liu et al/2019
Liu et al/2019
Chen et al/2019
Li et al/2018
Zhang et al/2018
Zhang et al/2018
Zong et al/2018
Li et al/2018
Combined
Li et al/2018
Zhu et al/2017
Figure 2: Forest plots of the sensitivity and specificity for circRNAs in diagnosing lung cancer.
2.31 [1.57 - 3.41] 0.34 [0.24 - 0.49]
0.26 [0.15 - 0.45]
0.36 [0.21 - 0.60]
0.39 [0.29 - 0.53]
0.48 [0.27 - 0.85]
0.38 [0.22 - 0.58]
0.27 [0.15 - 0.50]
0.15 [0.07 - 0.33]
0.22 [0.13 - 0.38]
0.33 [0.23 - 0.49]
0.31 [0.26 - 0.37]
Q = 11.30, df = 9.00, P = 0.26
I2 = 20.36 [0.00 - 76.67]
2.55 [1.77 - 3.65]
10.00 [2.56 - 39.06]
2.59 [1.66 - 4.02]
1.71 [1.13 - 2.56]
3.56 [1.93 - 6.57]
3.00 [1.81 - 4.98]
5.71 [2.86 - 11.41]
6.57 [3.25 - 13.30]
2.69 [1.91 - 3.80]
3.17 [2.43 - 4.14]
Q = 22.80, df = 9.00, P = 0.01
I2 = 33.18 [33.18 - 87.87]
1.1 39.1
DLR positive
0 1
DLR negative
Study ID DLR positive (95% CI) Study ID DLR negative (95% CI)
Liu et al/2019
Liu et al/2019
Chen et al/2019
Li et al/2018
Zhang et al/2018
Zhang et al/2018
Zong et al/2018
Li et al/2018
Combined
Li et al/2018
Zhu et al/2017
Liu et al/2019
Liu et al/2019
Chen et al/2019
Li et al/2018
Zhang et al/2018
Zhang et al/2018
Zong et al/2018
Li et al/2018
Combined
Li et al/2018
Zhu et al/2017
Figure 3: Forest plots of the positive likelihood ratio and the negative likelihood ratio for circRNAs in diagnosing lung cancer.
4 Disease Markers
3.2. Threshold Effect. The threshold effect was evaluatedwith the Spearman rank correlation. The Spearman corre-lation coefficient was 0.079 (P = 0:829), suggesting nothreshold effect.
3.3. Results of Meta-Analysis. Significant heterogeneity wasassessed using the random-effects model (I2 > 50%). For thevalue of circRNAs in diagnosing lung cancer, the pooled sen-sitivity, specificity, PLR, NLR, and DOR were 0.77 (95% CI:0.73–0.80; I2 = 8:98), 0.76 (95% CI: 0.69–0.82; I2 = 63:12%),3.17 (95% CI: 2.43–4.14; I2 = 33:18%), 0.31 (95% CI: 0.26–0.37; I2 = 20:36%), and 10.26 (95% CI: 6.87–15.31; I2 =97:18%), respectively. AUC was 0.78 (95% CI: 0.74–0.81).Forest plots and SROC are shown in Figures 2–5. Fagan’snomogram is shown in Figure 6. If the pretest probabilitywas 20%, the posttest probability increased to 44%. The pre-test likelihood ratio (LR) was 3%, and the posttest LRdecreased to 7%. The NLR was 0.31. An LR scattergramwas used to evaluate the clinical value of different diagnostictests and divided into four quadrants (Figure 7). All 10 eligi-ble studies were in the right lower quadrants, suggesting thatcircRNAs were useful in diagnosing lung cancer.
3.4. Regression Analysis. The I2 value was 96.84%, suggestingsignificant heterogeneity. The sample type, cancer type, refer-
ence gene type, and differential expression of circRNAs weretaken as potential causes of heterogeneity, and a metaregres-sion analysis was performed. No significant causes for het-erogeneity were found. The results are shown in Table 2.
3.5. Subgroup Analysis. A subgroup analysis was performedbased on the sample type, sample size, cancer type, referencegene type, and differential expression of circRNAs. Althoughthe sample size did not contribute to heterogeneity, the sen-sitivity, specificity, and DOR of blood samples were 0.72,0.78, and 9.32, while the corresponding values of tissue sam-ples were 0.80, 0.75, and 11.67, respectively. These findingssuggested that tissue circRNAs were slightly superior toblood circRNAs in diagnosis. The sensitivity, specificity,and DOR of the non-small-cell carcinoma subgroup were0.78, 0.70, and 9.66, while the corresponding values of thelung adenocarcinoma subgroup were 0.75, 0.80, and 12.54,respectively, suggesting the superiority of circRNAs in lungadenocarcinoma over those in non-small-cell carcinoma.The subgroup analysis of the reference gene was not con-ducted because only one study considered β-actin as the ref-erence gene. The results are shown in Table 3.
3.6. Publication Bias. The publication bias of the includedstudies was tested using Deeks’ funnel plot, and significantdifferences in the slope rate (P < 0:05) suggested the publica-tion bias. The funnel plot was constructed with the Stata 12.0software (Figure 8), and the results showed no publicationbias (P = 0:24).
Study ID
6.74 [3.42 - 13.31]
9.76 [4.37 - 21.81]
28.00 [5.52 - 141.91]
6.65 [3.33 - 13.29]
3.57 [1.40 - 9.09]
9.85 [3.72 - 26.08]
11.00 [4.11 - 29.45]
37.14 [11.46 - 120.42]
29.87 [10.68 - 83.56]
8.08 [4.18 - 15.63]
10.26 [6.87 - 15.31]
Q = 313.60, df = 9.00, P = 0.00
I2 = 97.18 [96.24 - 98.11]
Liu et al/2019
Liu et al/2019
Chen et al/2019
Li et al/2018
Zhang et al/2018
Zhang et al/2018
Zong et al/2018
Li et al/2018
Combined
1 142
Odds ratio
Li et al/2018
Zhu et al/2017
Odds ratio (95% CI)
Figure 4: Forest plots of the diagnostic odds ratio for circRNAs indiagnosing lung cancer.
SROC with prediction & confidence contours1.0
0.5
0.01.0 0.5 0.0
Observed dataSummary operating pointSENS = 0.77 [0.73 - 0.80]SPEC = 0.76 [0.69 - 0.82]SROC curveAUC = 0.78 [0.74 - 0.81]
95% confidence contour95% prediction contour
Specificity
Sens
itivi
ty
3
2 4 910
758
61
Figure 5: Summary receiver operating characteristic curve forcircRNAs in diagnosing lung cancer.
5Disease Markers
4. Discussion
The present meta-analysis enrolled 8 studies from 2017 to2019 and systemically reviewed 10 circRNAs in diagnosinglung cancer. The results showed that the AUC was 0.78,and the pooled sensitivity, specificity, and DOR were, respec-tively, 0.77 (95% CI: 0.73–0.80), 0.76 (95% CI: 0.69–0.82),and 10.26 (95% CI: 6.87–15.31). The findings suggested thediagnostic value of circRNAs for lung cancer. The includedstudies involved only a preliminary analysis of the role ofone or two circRNAs in diagnosing lung cancer, with smallsample size and sensitivity varying from 0.511 to 0.884(lower than pooled sensitivity in six studies), specificity from0.575 to 0.933 (lower than pooled specificity in six studies),and AUC from 0.643 to 0.897 (lower than or equal toAUC in this meta-analysis in five studies). The sensitivity,specificity, and AUC fluctuated largely among these studies,possibly due to the involvement of one or two circRNAs andsmall sample size.
The Spearman correlation coefficient was calculated totest the threshold effect and was 0.79 (P = 0:829), suggestingthat the threshold effect was not the cause of heterogeneity.In addition, the regression analysis of sample type, lungcancer type, reference type, and differential expression ofcircRNAs showed that these factors did not cause heteroge-neity. The causes of heterogeneity could not be directly foundusing the studies included in this analysis. Neither study was
a randomized controlled study, possibly leading to heteroge-neity. However, this hypothesis should be further verified.Additionally, the present meta-analysis included 8 studiesand systematically reviewed the value of 10 different cir-cRNAs in diagnosing lung cancer. The analysis revealed thatthe expression levels of these circRNAs were different, whichmight be one of the sources of heterogeneity and also a com-mon problem in this type of analysis.
In conclusion, this systematic review of data extractedfrom eight studies showed the value of circRNAs in diagnos-ing lung cancer. These studies were primarily based on thetesting of lung cancer tissues. Blood and exocrine secretions
100
LUQ: exclusion & confirmationLRP>10, LRN<0.1RUQ: confirmation onlyLRP>10, LRN>0.1LLQ: exclusion onlyLRP<10. LRN<0.1RLQ: no exclusion or confirmationLRP<10, LRN>0.1
with 95% confidence intervalsSummary LRP & LRN for index test
10
11
Negative likelihood ratio
2
9110
7
9
6
4
8
3
Figure 7: A likelihood ratio scattergram.
Table 2: Relative diagnostic odds ratio of covariants in themetaregression analysis.
RDOR 95% CI P value
Sample type 2.07 (0.62–6.95) 0.1710
Cancer type 1.38 (0.41–4.67) 0.5064
Reference 0.27 (0.04–1.63) 0.1125
Expression of circRNAs 0.81 (0.21–3.18) 0.6918
0.1
0.20.30.50.7
1
2357
Likelihood ratio
10005002001005020105210.50.20.10.050.020.010.0050.0020.001
10
203040506070
Pre-
test
prob
abili
ty (%
)
Post-
test
prob
abili
ty (%
)
80
909395979899
99.399.599.799.899.9 0.1
Prior prob (%) = 20LR_Positive = 3Post_Prob_Pos (%) = 44LR_Negative = 0.31Post_Prob_Neg (%) = 7
0.20.30.50.71
235710
20304050607080
90939597989999.399.599.799.8
99.9
Figure 6: Fagan’s nomogram for likelihood ratios.
6 Disease Markers
were less used, and clinical data were limited. Therefore, therelationship of circRNAs in the blood or exocrine secretionswith lung cancer needs further investigation, and the findingmight help in the development of molecular markers of diag-nosis and prognosis. Further, the recent studies explored therole of a single circRNA in diagnosing and treating cancerusing a small sample size; no multicenter and large-samplestudies were reported. Hence, the diagnostic accuracy andstability of circRNAs need further elucidation.
Conflicts of Interest
The authors declared that they have no conflict of interests.
Acknowledgments
This study was supported by Guangdong MedicalResearch Fund Project (A2018164) and Guangdong Prov-ince General University Characteristic Innovation Project(2018KTSCX185).
References
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Table 3: Summary results of the subgroup analysis for circRNAs in diagnosing lung cancer.
Number ofstudies
Sensitivity(95% CI)
Specificity(95% CI)
PLR (95% CI) NLR (95% CI) DOR (95% CI) AUC
Sample size
Blood 4 0.72 (0.66–0.78) 0.78 (0.66–0.87) 3.30 (2.12–5.15) 0.35 (0.29–0.43) 9.32 (5.35–16.23) 0.78
Tissue 6 0.80 (0.75–0.84) 0.75 (0.66–0.82) 3.16 (2.22–4.49) 0.27 (0.20–0.36) 11.67 (6.36–21.39) 0.84
Lung cancer
Non-small-celllung cancer
6 0.78 (0.73–0.83) 0.70 (0.66–0.79) 2.87 (2.22–3.72) 0.30 (0.23–0.38) 9.66 (6.00–15.55) 0.82
Lung adenocarcinoma 4 0.75 (0.69–0.79) 0.81 (0.68–0.90) 3.93 (2.20–7.03) 0.31 (0.25–0.40) 12.54 (5.96–26.39) 0.76
Reference gene
GAPDH 9 0.76 (0.72–0.79) 0.75 (0.68–0.81) 3.00 (2.31–3.90) 0.33 (0.28–0.38) 9.41 (6.66–13.31) 0.77
circRNA expressionupregulation
8 0.76 (0.72–0.80) 0.77 (0.69–0.84) 3.38 (2.39–4.77) 0.31 (0.25–0.38) 10.96 (6.57–18.29) 0.79
Note: PLR: positive likelihood ratio; NLR: negative likelihood ratio; AUC: area under the receiver operating characteristic curve.
6
5 4 3
8
2
9
1
10
.06
Deek’s funnel plot asymmetry testP value = 0.24
StudyRegressionline
.08
.1
.12
.141 10 100 1000
Diagnostic odds ratio
1/ro
ot (E
SS)
Figure 8: Deeks’ funnel plot evaluating the potential publicationbias of the included studies.
7Disease Markers
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